Haloalkanoyltetrahydroisoquinolinecarbo-xylic acid esters

ABSTRACT

Ethyl 2-( Alpha -halo lower-alkanoyl)-1,2,3,4-tetrahydro-6,7dimethoxy-1-isoquinolinecarboxylates are intermediates for the preparation of 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2Hpyrazino(2,1-a)isoquinolines, which possess sedative, tranquilizing and related pharmacodynamic effects.

United States Patent Archer et a1.

[451 July 11, 1972 [54] HALOALKANOYLTETRAHYDROISOQ UINOLINECARBO-XYLICACID ESTERS [72] Inventors: Sydney Archer; John W. Schulenberg, both ofBethlehem, NY.

[73] Assignee: Sterling Drug Inc., New York, NY.

[22] Filed: April 8, 1970 [21] Appl. No.: 26,766

Related US. Application Data [60] Division of Ser. No. 826,681, May 21,1969, Pat. No. 3,557,120, which is a continuation-in-part of Ser. No.569,021, Aug. 1, 1966, abandoned.

52 us; C1. ..260/287 R [51] Int. Cl. ...C07d 35/32 [58] Field of Search..268/387 [56] References Cited UNITED STATES PATENTS 3,015,662 6/1962Georgian ..260/287 X Kametani et a1. Jour. Pharm. Soc. Japan Vol. 86, p.9735 (Oct. 1966) Walters et al., Chem. Abstr. Vol. 55 C01. 21 122; 1961)Gardent Chem. Abstr. Vol. 50 C01. 10724 1955) Primary Examiner-Donald G.Daus A!t0rneyElmer J. Lawson, B. Woodrow Wyatt, Thomas L. Johnson,Robert K. Bair, William G. Webb and Roger T. Wolfe [5 7] ABSTRACT Ethyl2-(a-ha1o lower-a1kanoy1)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxylates are intermediates for thepreparation of 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-pyrazino[2,l-a]isoquino1ines, which possess sedative, tranquilizingand related pharmacodynamic effects.

2 Claims, No Drawings and HALOALKANOYLTETRAHYDROISOQ UINOLINECARBO-XYLICACID ESTERS Thisapplication is a division of our copending applicationSer. No. 826,681, filed May 21, 1969, now US. Pat. 3,557,120 which is inturn a continuation-impart of our application Ser. No. 569,021, filedAug. 1, l966, copending with said application Ser. No. 826,681 and nowabandoned.

Our invention relates to derivatives of l,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, to intermediates for the same, to derivativesof the intermediates and to the preparation thereof.

The novel compounds of this invention are defined by the structuralformula C H: H300 moo- N N I HzhnPhenyl in which Y IS 1:! or 1:2alkylene of up to (and including) six carbon atoms and m is zero, one ortwo.

More specifically, the compounds of our invention are 2-[phenyl(CH),,,]-3-(R',R )-l,3,4,6,7,llb-hexahydro-9,ldimethoxy-2H-pyrazino[2,l-a]isoquinolines which, in thefree base form, are defined by the formula -[P Y 2)..l-4-(R,R 1,3,4,6,7,l lb-heitahydro- 9, l0-dimethoxy-2H-pyrazino[2,l-a]isoquinolines defined, in the free baseform, by the formula In each of the formulas, Ill, and W, m has themeanings given hereinabove. The symbols R and R used in the formulas Illand IV, represent hydrogen or lower-alkyl of up to (and ineluding) fivecarbon atoms.

As used herein, the term 1:1 alkylene" means an alkylene group havingboth free valence bonds on the same carbon atom, as illustrated by, butnot limited to, methylene, 1,1-

ethylene, l,l-propylene, 2,2-propylene, l,l-butylene, 2,2-butylene,l,l-isobutylene, l,l-neopentylene, 3,3-hexylene, and the like, and 1:2alkylene" means an alkylene group having one free valence bond on onecarbon atom and the other on the carbon atom adjacent to the said carbonatom, as illustrated by, but not limited to, l,2-ethylene,1,2-propylene, 2,3- butylene, l,2-isobutylene, 2,3-hexylene,2,3-isopentylene, l,2-neohexylene, and the like.

As used throughout, the term lower-alkyl" means saturated, monovalenthydrocarbon groups including straight and branched-chain groups asillustrated by, but not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, and the like. Lower-alkyl groups of from one tothree carbon atoms are preferred.

The benzene ring of the terms phenyl," phenyl-lower-alkyl," andphenyl(CH,),,, as used throughout this disclosure can bear any numberand kind of substituents such as would occur to those skilled in theart. The presence of such substituents on the benzene ring does notadversely affect the pharmacological activity of the compositions ofthis invention. Preferred among such substituted-benzene rings are,without limiting the generality of the foregoing, monosubstituted phenylwherein the substituent is in any of the possible orientations in thering, for example, lower-alkylphenyl, e.g., methylphenyl, ethylphenyl,isopropylphenyl; halophenyl, e.g., fluorophenyl, chlorophenyl,bromophenyl, iodophenyl; loweralkoxyphenyl, e.g., methoxyphenyl,ethoxyphenyl, butoxyphenyl; trifluoromethylphenyl;lower-alkylthiophenyl, e.g., methylthiophenyl, butylthiophenyl; orN,N-di-lower-alkylaminophenyl, e.g., N,N-dimethylaminophenyl, N-Methyl-N-ethylaminophenyl. In the aforementioned groups, loweralkyl orlower-alkoxy can have from one to four carbon atoms. Thus the termPhenyl in Formulas I instead, Ill-VI and VIll-XVll can be eitherunsubstituted or substituted by a member of the group consisting oflower-alkyl, lower-alkoxy, halogen, halo-lower-alkyl, lower-alkylthio orN ,N-di-lower-alkylamino.

The term phenyl-lower-alkyl as used throughout means a monovalentradical consisting of the phenyl nucleus bonded to the rest of themolecular through a divalent lower-alkylene radical of from one to fourcarbon atoms as exemplified by, but not limited to, methylene,l,l-ethylene, l,2-ethylene, 1,3- propylene, l,2-propylene, 1,4-butylene,and the like. Thus, solely for illustration and without limitation,examples of phenyl-lower-alkyl are phenylmethyl, l-phenylethyl,2-phenylethyl, 3-phenylpropyl, and the like.

Pharmacological evaluation of the compounds of Formulas Ill, and IV hasshown that they possess pharmaco-dynamic properties, in particular,central nervous system depressing, sedative, and anti-convulsantactivities thus indicating their usefulness as C.N.S. depressants,sedatives, and anti-convulsants.

C.N.S. depressant activity for the compounds of the instant inventionwas determined in standard activity cages using the method of Dews,Brit. J. PharmacoL, 8, 46(l953)in which mice, medicated with the testcompounds, are placed in wire mesh cages equipped with a photoelectriccell so adjusted that a mouse breaking the beam activates a magneticdigital counter. Thus the number of times the light beam is broke over aperiod of time is an indication of the motor activity of the animals,and a reduction in the number of counts in the medicated mice overcontrol groups, run simultaneously, is taken as evidence of psychomotordepressant activity. The dose at which such reduction in motor activitywas observed was recorded as the active dose. Thus when administered bythe oral route in doses of from about 100 to about 300 milligrams perkilogram, of body weight the 2-[phenyl(Cl l ),,,]-3 (or 4)-(R',R )-l,3,4,6,7,l lb-hexahydro-9,IO-dimethoxy-ZH- pyrazino [2, l-alisoquinolinesof Formula Ill and IV decreased the spontaneous activity of the mice byabout 60 to about percent. The preferred pyrazino [2,l-a]isoquinolinesof the instant invention, Z-phenethyl-l ,3,4,6,7,l lb-hexahydro-9, l 0-dimethoxy-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, described inExample 11, and 2-phenyl-l,3,4,6,7,llb-hexahydro-9,1O-dimethoxy-2H-pyrazino[2,l-a]isoquino1inedihydrochloride described in Example 9, were found to decreasespontaneous activity by about 60 percent and about 80 percentrespectively at dose levels of 100 mg./kg.

Sedative activity of the compounds was determined using the standardhexobarbital potentiation test which is described briefly as follows.The compounds, in the form of their hydrochloride salts in distilledwater, were administered either orally or intraperitoneally into threegroups of 10 white Swiss mice at each of three different dose levelsgraduated in geometric progression in multiples of two. Forty minutesafter medication, the animals were each administered a subhypnotic doseof 40 mg./kg. of hexobarbital given either orally (p.o.) orintraperitoneally (i.p.). The animals in each group were then examinedevery five minutes for a period of fifteen minutes for loss of therighting reflex. The number of animals in each group that sufiered lossof the righting reflex for at least 1 minute was noted, and suchcompounds were considered active, and the dose which produced loss ofthe righting reflex in 50 per cent of the animals was called theEffective Dose (ED 2 phenyl-l,3,4,6,7,l lb-hexahydro-9,l-dimethoxy-2H-pyrazino[2,1-a]isoquinoline described in Example 9below was found to have an ED of 30 i 7.4 mg./kg.

Anticonvulsant activity was determined using the standard maximalmetrazol-induced seizures procedure described by Goodman et al., J.Pharm. Exp. Therap. 108, 168 (1953). In this procedure, convulsions areinduced in untreated mice by the intravenous injection of 50 mg./kg. ofmetrazol. A group of mice is pretreated with the substance to be testedthirty minutes before receiving metrazol intravenously, and the animalis considered protected and the drug active if the drug prevents thehindleg tonic extensor component of the seizure. The dose which protects50 per cent of the treated animals for a period of 90 minutes aftermedication is called the Effective Dose (ED Thus 2-phenethyl-l,3,4,6,7,llb-hexahydro- 9,l0-dimethoxy-2H-pyrazino[2,l-a]isoquinolinedihydrochloride, described in Example 1 1 below, was found to preventthe hindleg tonic extensor component of the seizure at a dose level of50 mg./kg. (i.p.) and the ED of 2-phenyll,3,4,6,7,l lb-hexahydro-9, lO-dimethoxy2H-pyrazino[ 2, l a]isoquinoline dihydrochloride, describedin Example 1 1 below, was found to prevent the hindleg tonic extensorcomponent of the seizure at a dose level of 50 mg./kg. (i.p.) and theED, of 2-phenyl-l,3,4,6,7,l lb-hexahydro-9,l0-dimethoxy-2l-l-pyrazino[2, 1 -a]isoquinoline dihydrochloride, describedin Example 9 hereinbelow, was found to be 57 mg./kg. (i.p.).

The compounds of formula [II and IV were found to be pharmacologicallyactive at dose levels well below dose levels manifesting evidence ofacute toxicity.

The actual determination of the numerical biological data definitive fora particular compound is readily obtained by the above-describedstandard test procedures by technicians trained in pharmacological testmethods, without the need for any extensive expermentation.

The intermediate, hydro-8,9-dimethoxy-imidazo[5,1- a]isoquinolines ofFormula II, l-[N-(phenylline, is represented by the formula CH; 5 4 I H3cm II CO \(JII 511, V ITl(CH2)mPhon vl wherein m is zero, one or two,with a carbonyl compound such as an aldehyde or a ketone.

The intermediate, l-[N-(phenyl(CH),,,)laminomethyll,3,3,4-tetrahydro-6,7-dimethoxyisoquinoline, offormula V,

can be prepared by lithium aluminum hydride reduction of N- [phenyl(CH--l .2 .3 .4-tetrahydro 6.7-dimethoxy I -isoquinolinecarboxamide of theformula in which m is zero, one or two.

The N-[phenyl(CH-),,,]-l,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinecarboxamide (Vl)used as an intermediate in preparing the pyrazinoisoquinolines of ourinvention, is prepared by reacting ethyll,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinecarboxylate, known in theprior art, with phenyl(CH ),,,amine, wherein m has the meanings givenhereinabove. The reaction is preferably carried out at a temperaturebetween about 75 C. and 225 C. either without a solvent or with asolvent inert under the conditions of the reaction. Such solvents are,for example, benzene, toluene, or xylene. It is preferable, but notnecessary, to carry out the reaction under an atmosphere of nitrogen,and in the presence of a sodium or potassium alkoxide, for example,potassium tert-butoxide.

Alkylated ring-nitrogen derivatives of the intermediate, N- lphenyhHslml-l ,2.3.4-tetrahydro-6.7-dimethoxyl -isoquinolinecarboxamide,represented by the formula l III-(C H Phenyl H VIII where in bothformulas R is lower-alkyl or phenyl-lower-alkyl, can be prepared by thereaction of the compounds of formula VI and formula V respectively, withlower-alkyl and phenyllower-alkyl esters of strong mineral acids. By wayof illustration and without being limited thereto, there can bementioned lower-alkyl chlorides, lower-alkyl bromides, phenyllower-alkylbromides, lower-alkyl sulfates, phenyl-lower-alkyl sulfates, and thelike. Alternatively, lower-alkyl and phenyllower-alkyl esters of strongorganic sulfonic acids can be used, for example, lower-alkyl andphenyl-lower-alkyl methanesulfonates and toluenesulfonates. The reactionis preferably carried out in refluxing acetonitrile in the presenceofsodium carhonztte.

When 1-[N-(phenyl(CH ),,,)]aminomethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (V) is reacted with an a-halolower-alkanoyl halide at a temperature of about -l C. to 10 C. in thepresence of anhydrous sodium carbonate,

The intermediate, V, prepared as described hereinabove, is reacted witha phenylmethyl halide in the presence of an acidacceptor, for example,sodium carbonate or potassium carbonate. The reaction is preferablycarried out in refluxing and in a solvent inert under the conditions ofthe reaction, flcetonitfile- T0 the resulting -(P "y z)m)l there isobtained l-[N-(a-halo lower-alkanoyl)-N-(phenm yl- -beyl-l,2,3.4-tetrahydro-6,7-dimethoxyisoquinyl(CI-I),,,)]aminomethyl-2-(a-halo lower-alkanoyl)-l,2,3,4- oline (XI), thereis then slowly added at a temperature oftetrahydro-6,7-dimethoxyisoquinoline of the formula about 'l0 C. ana-halo lower-alkanoyl halide in a solvent inert under the conditions ofthe reaction. Suitable solvents are, for example, chloroform, methylenedichloride or carbon tetrachloride. The l-[N-(a-halolower-alkanoly)-N-(phen- C II: yl(CH ]-aminomethyl-2-benzyl-l,2,3,4-tetrahydro-6,7- H100 zu, X dimethoxyisoquinoline hydrohalide thusobtained, is con- I\|I L/ verted to its base, XII, by treatment at atemperature of about H300- 0 C. with aqueous alkali, and said base isthen heated in a i lower-alkanol comprised of from one to three carbonatoms, CH, for example, methanol, ethanol, or isopropanol. Without Iisolation, the lower-alkanol solution of the cyclized com- N-C0tb pound,XIII, can be subjected to debenzylation by catalytic hydrogenolysis togive the carbonyl intermediate XIV, which can be reduced with lithiumaluminum hydride to give a com- X CI-I:)mPheny1 pound represented byformula IV. 4

The 3-oxo-2-[phenyl(CI'I ),,,]-4-(R,R )-l,3,4,6,7,llb-hexahydro-9,10-dimethoxy-2H-pyrazino[2,l-a]isoquinolines of 1 2 h d I1k 1 Formula XIV in addition to having utility as intermediates forwheremR andR are y rogen or ower-a y ,mls zero, one the preparation ofthe 2 [phenyl(CH2)m] 4 (R,,R2) or two, and X IS bromine or chlorine.Suitable solvents for this 1 3 4 6 7 l lb hexahydro 9 l0 dimethXy 2HpyraZino[2 g 3 gg fgz gfig fgfgg dlchlonde' a]isoquinolines of FormulaIV, have been found to possess zs fissd liferein the term oz-halolower-alkanoyl includes g z g g lg 2 g" wlen tesfed f g g to the met 0 oews escn e a ove. xemp aryo t e -oxoin- 222m;1:21aizasmxmix tfi213,222:2iif by chloroacetyl, a-bromoacetyl, a-bromopropionyl, a-chlorobuz giziiis zzgggfigi g i z ig 31:23:; g' if i gfi g a'chloro'a'methylproplonyl35 under E-2 in the section detailing preparation of interfg iffig n 1 32;, H 3 4 6 7 llb hcxahydro mediates hereinbelow. When administered at300 mgJkg. 9 l0 dime t hoxy 2H p yi azino[2 l a]isbciuinblines (IV) ofthis Joxozuehloropheni'l)l3467l lbhexahydm'9,10-dimeth0xy-2H-pyrazino[2,l-a]isoquinoline decreased ""Zl'f":lvir'ii'i 'ri i5 ld fivi ?l" 2,212,223 activity by about Percentlii ieiniibove and X is halo en preferably bromine or 40 The lbmexahydm hl g9,10-dimethoxy-2l-I-pyrazino[2,l-a]isoquinolines (III) of our 0 orme'invention can be prepared by lithium aluminum hydride reduction ofl,4-dioxo-2-[ phenyl( CH ),,,]-3-( R',R l,3,4,6,7,l lb-hexahydro-9, l0-dimethoxy-2H-pyrazino[2, l-a] 2 isoquinoline of the formula CH 2 H3CO\CH2 /1-C OX H CO /Cg2 V C5H5CH2X R1 3 CH2 I{3CO NOH2COH5 Ill 0 C IIQCO5 i v 0:0 0 13H H XI HQ PhneyI CH XV fim y C 2 2 H300 (3H2 H3CO CH2 X6N-CH2C6H5 HQCO ofi A Haco N CHQ o s (1H2 X R2 0% C 1-l I'm 4 l R R1 CHi=0 i \2 XII H2)mPheny1 l XIII (CH Il1onyl (3E2 CO H2 H3 (1H2 wherein m,Rand R have the meaning given heremflbove- H3CO N R LiA1H4 v The1,4-dioxo intermediate supra, is prepared by alternate fi c i I methods,starting with the known ethyl I,2,3,4- tetrahydrol6,7-dimethoxy-l-isoquinolinecarboxylate. In one of the E methods, theester is reacted with a-halo lower-alkanoyl haf lide, preferably inchloroform solution at a temperature of XIV (()1Iz),..1henyl about l0 C.to about l0 C. followed by refluxing for 3 to 5 7 hours. The ethylZ-(a-halo lower-alkanoyl)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate of the formula XVIwherein m is zero, one or two and R and R are hydrogen or lower-alkyl,and X is bromine or chlorine is then reacted with phenyl(CH ),,,amine,wherein m has the meanings given above, preferably at a temperature ofabout190 C. to 210 C. for a period of 30 to 70 hours in a solvent, inertunder the conditions of the reaction to give the 1,4-dioxo intermediate.A preferred solvent is diethylene glycol monoethyl ether.

Another method for the preparation of the 1,4-dioxo intermediate (XV)comprises the reaction of N-[phenyl(CHl,2,3,4tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide (VI),described hereinabove, with an a-halo lower-alkanoyl halide inchloroform solution preferably at a temperature of about -l C. to C.followed by reflux for l to 5 hours. The N-[phenyl(CI-I ),,,]-2-(a-haloloweralkanoyl)-l,2,3,4-tetrahydro-6,7-dimethoxy-I-isoquinolinecarboxamide, thus obtained andhaving the formula wherein m, the R, R and X have the meanings givenabove, is reacted with sodium hydride in a refluxing hydrocarbonsolvent, preferably at a temperature of about 75 C. to about 150 C. forl to 3 hours to obtain the intermediate 1,4-dioxo- 2-[phenyl(CH),,,]-3-(R',R )-l,3,4,6,7,l lb-hexahydro-9,l0- dimethoxy-2H-pyrazino[2,1-a]isoquinoline (XV).

In addition to being useful as intermediates for the preparation of the2-[phenyl(CH ]-3-(R,R)-l,3,4,6,7,1lb-hexahydro-9,I0-dimethoxy-2H-pyrazino[2,I-a]isoquinolinesof Formula III above, the l,4-dioxo-2-[phenyl(Cl I ),,,]-3-(R,R)-l,3,4,6,7,l lb-hexahydro-9,I0-dimethoxy-2H-pyrazino[2,1-a]isoquinolines of Formula XV have been found to substantially decreasespontaneous activity when tested according to the method of Dewsdescribed hereinabove. Thus a preferred member of the group of compoundsrepresented by Formula XV, l,4-dioxo-2-phenylmethyll ,3,4,6,7,Ilb-hexahydro- 9,l0-dimethoxy-2H-pyrazino[2,l-a]-isoquinoline, describedunder F-IO in the section detailing preparation of intermediateshereinbelow, was found to decrease spontaneous activity by about 64percent when administered at a dose level of 300 mg/kg. (p.o.).

The novel compounds of the instant invention are the bases representedby the general formulas III, and IV as well as the intermediates andderivatives of the intermediates represented by the formulas V VI andVIII XVII, given hereinabove and the acid-addition salts of said bases,and said acid-addition salts are the full equivalents of the free bases.The compounds of the invention in free base form are converted to theacidaddition salt form by interaction of the base with an acid.Conversely, the free bases can be regenerated from the acid-additionsalt form in the conventional manner, that is by treating the salts withstrong aqueous bases, for example, alkali metal hydroxides, alkali metalcarbonates and alkali metal bicarbonates. The bases thus regenerated canthen be interacted with the same or a different acid to give the same ora different acid-addition salt. Thus the novel bases and all of theiracidaddition salts are readily interconvertible.

It will thus be appreciated that the general formula shown above notonly represents the structural configurations of the bases of ourinvention but is also representative of the respective structural entitywhich is common to all of our respective compounds, whether in the formof the free bases or in the form of the acid-addition salts of thebases. We have found that by virtue of this common structural entity,the bases and their acid-addition salts have inherent pharmaco-dynamicactivity of the type described hereinabove. This inherentpharmacodynamic activity can be used for pharmaceutical purposes byemploying either the free bases or the acid-addition salts formed withpharmaceutically-acceptable acids, that is, acids whose anions areinnocuous to the animal organism in effective doses of the salts so thatbeneficial properties inherent in the common structural entityrepresented by the free bases are not vitiated by side-effectsascribable to the anions.

In utilizing this pharmacodynamic activity of the salts of theinvention, we prefer of course to use pharmaceutically-acceptable salts.Although water-insolubility, high toxicity, or lack of crystallinecharacter may make some particular salt species unsuitable or lessdesirable for use as such in a given pharmaceutical application, thewater-insoluble or toxic salts can be converted to the correspondingpharmaceutically-acceptable bases by decomposition of the salt withaqueous base as described above, or alternatively they can be convertedto any desired pharmaceutically-acceptable acid-addition salt by doubledecomposition reactions involving the anion, for example, byion-exchange procedures,

Moreover, apart from their usefulness in pharmaceutical applications,our salts are useful as characterizing or identifying derivatives of thefree bases or in isolation or purification procedures. Like all of theacid-addition salts, such characterizing or purification saltderivatives can, if desired, be used to regenerate thepharmaceutically-acceptable free bases by reaction of the salts withaqueous base, or alternatively they can be converted topharmaceutically-acceptable acid-addition salts by, for example,ion-exchange procedures.

It will be appreciated from the foregoing that all of the acidadditionsalts of our new bases are useful and valuable compounds, regardless ofconsiderations of solubility, toxicity, physical form, and the like.

The novel feature of the compounds of the invention, therefore; residesin the concept of the bases and cationic forms of the 2-[phenyl(CI-I),,,]-3-(R,R )-l,3,4,6,7,IIb-hexahydro-9,10-dimethoxy-2H-pyrazino[2,l-a]isoquinolines (III) and the2-[phenyl(CH ),,,]-4-(R,R )-1,3,4,6,7,1lb-hexahydro-9,10-dimethoxy-2I-I-pyrazino[2,l-a]isoquinolines (IV), the intermediatesfor the preparation thereof, and the derivatives of said intermediates(V VI and VIII XVII), and not in any particular acid anion associatedwith the salt forms of the compounds, rather, the acid anions, which canbe associated in the salt forms, are in themselves neither novel norcritical and therefore can by any acid anion or acid-like substancecapable of salt formation with bases. In fact, in aqueous solutions thebase form or water-soluble acid-addition salt form of the compounds ofthe invention both possess a common protonated cation or ammonium ion.

The acid-addition salts are prepared either by dissolving the free basein an aqueous solution containing the appropriate acid and isolating thesalt by evaporating the solution, or by reacting the free base and acidin an organic solvent, in which case the salt separates directly or canbe obtained by concentration of the solution.

The compounds can be prepared for use by dissolving, under sterileconditions, a salt form of the compounds in water (or an equivalentamount of a non-toxic acid if the free base is used), or in aphysiologically compatible aqueous medium such as saline, and stored inampoules for use by injection. Alternatively, they can be incorporatedin unit dosage form as tablets or capsules for oral administration or incombination with suitable adjuvants such as calcium carbonate, starch,lactose, talc, magnesium stearate, gum acacia, and the like. Stillfurther the compounds can be formulated for oral administration inaqueous alcohol, glycol, oil solution or oil-water emulsions, or otherconventional pharmaceutical excipients.

The chemical structures of the compounds of the invention areestablished by their mode of synthesis and are corroborated by thecorrespondence between calculated values for the elements and valuesfound by chemical analysis and by concordant spectral properties.

The following procedures and examples will further illustrate specificembodiments of the invention.

PREPARATION OF INTERMEDIATES AND DERIVATIVES THEREOF A. N-[Phenyl(CI-I),,,]-2-(R)-l,2,3,4-tetrahydro-6,7- dimethoxy-1-isoquinolinecarboxamides[V], R H; VIII, R lower-alkyl and phenyllower-alkyl; XVII, R (oz-haloloweralkanoyl)].

1. A mixture of 2.7 g. (0.0] mole) of ethyl l,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate and 5.0 ml. (0.05mole) of aniline was heated to reflux for one and one-half hours whiledistilling off about 3 ml. of solvent. The residue. was taken up in ml.of absolute ethyl alcohol and the solution cooled to giveN-phenyl-l,2,3,4-tetrahydro-6,7- dimethoxy-lisoquinolinecarboxamidewhich when recrystallized, from absolute ethyl alcohol, melted at l62l65C. The hydrochloride salt, prepared by treatment of the free base withan ethyl alcohol solution of anhydrous hydrochloric acid, melted at237.0-245.0 C. (dec.)(corr.).

2. Following the procedure described in A-l hereinabove, butsubstituting N,N-dimethyl-p-phenylenediamine, in molar equivalent amountfor the aniline used in that procedure, there is obtainedN-(4-dimethylaminophenyl)-l,2,3,4- tetrahydro-6,7-dimethoxyl -isoquinolinecarboxamide.

3. A mixture of 4.0 g. (0.015 mole) of ethyl l,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate and 10.0 ml. (0.1mole) of benzylamine was refluxed for 17 hours. The mixture was taken upin hot ethyl acetate causing N-phenylmethyl- 1,2,3,4-tetrahydro-6,7-dimethoxyl -isoquinolinecarboxamide to crystallizespontaneously. Upon collection and recrystallization from boiling ethylacetate, the product, while solid, melted at 160-l62 C.

4. When the procedure of A-3 described above is used for the reaction ofethyl l,2,3,4-tetrahyro-6,7-dimethoxy-1- isoquinolinecarboxylate withphenethylamine, N-phenethyll,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinecarboxamide is obtained.

5. Using the procedure described in A-l hereinabove, but substituting4-(methylthio)aniline for the aniline used in that procedure, there isobtained N-( 4-methylthiophenyl)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxamide.

6. A suspension of 10.6 g. (0.04 mole) of ethyl 1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate, 6.4 g. (0.05 mole)of 4-chloroaniline and 4.9 g. (0.044 mole) of potassium t-butoxide in40.0 ml. of toluene was stirred and refluxed for 6 hours. To the mixturewas then added 50 ml. of water. After stirring for one-quarter of anhour, all of the solids had dissolved. The layers were separated and theaqueous layer was extracted with chloroform. The combined organic layerswere dried (MgSO The solvent was removed and the residual brown oil wastaken into 75 ml. of anhydrous ether causing a solid to separate. Thesolid was collected and recrystallized from boiling absolute ethylalcohol to give N-( 4- chlorophenyl)- l,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinecarboxamide as a white solid m.p. 121.4-l25.8 C. (corr.).

7. Following the procedure of A-6 above, but substituting4-bromophenylmethylamine for the 4-chloroaniline used in that procedure,there is obtained N-(4-bromophenyl)methyll,2,3,4-tetrahydro-6,7-dimethoxy- 1 -isoq uinolinecarboxamide.

8. Substituting 4-methylphenylmethylamine in molar equivalent quantityfor 4-chloroaniline, in the procedure described in A-6 hereinabove,there is obtained N-(4-methylphenylmethyl)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxamide.

9. Reacting ethyl l,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxylate with 4-methoxyaniline, according to theprocedure followed in A-6, affords N-(4-methoxyphenyl)-l,2,3,4-tetrahydro-6,7-dimethoxyl -isoquinolinecarboxamide.

10. When 4-butoxyphenethylamine, ethyl l,2,3,4-tetrahydro-6,7-dirnethoxyl -isoq uinolinecarboxylate and potassiumtbutoxide are reacted in toluene suspension according to the procedureof A-6 hereinabove, N-(4-butoxyphenethyl)- l,2,3,4-tetrahydro-6,7-dimethoxyl -isoquinolinecarboxamide is obtained.

1 l. The reaction of ethyll,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinecarboxylate with3-methoxyphenethylamine and in the presence of potassium t-butoxide in amanner analogous to procedure A-6 above, produces N-(3-methoxyphenethyll ,2, 3,4-tetrahydro-6,7-dimethoxyl -isoquinolinecarboxamide.

12. A stirred mixture of 9.36 g. (0.03 mole) ofN-phenyll,2,3,4-tetrahydro-6,7-dimethoxyl -isoquinolinecarboxamide, 6.14g. (0.033 mole) of methyl p-toluenesulfonate and 3.8 g. (0.036 mole) ofsodium carbonate in 75 ml. of acetonitrile was refluxed for four hours.Chloroform and water were added to the cooled reaction mixture and thelayers separated. The aqueous layer was extracted with additionalchloroform. The chloroform extracts were dried (Mg- SO,) and the solventremoved. A white solid remained, which was subjected torecrystallization from boiling absolute ethyl alcohol to giveN-phenyl-2-methyl-1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide, m.p. 175.0-l77.0 C. (corr.).

13. When ethyl2-methyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxylate andaniline are caused to react after the procedure of A-l as describedabove, N-phenyl-Z- methyl-l ,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinecarboxamide, having the same melting point as that obtainedin A-l 2 above, is obtained.

14. The reaction of N-phenethyl-l,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide with benzyl chloride in the presenceof sodium carbonate, carried out in refluxing acetonitrile, givesN-phenethyl-2-phenylmethyl-l,2,3,4- tetrahydro-6,7dimethoxy l-isoquinolinecarboxamide.

15. To a stirred chilled solution of 5.0 g. (0.016 mole) of N-phenyl-l,2,3,4 -tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide therewas added in portions 2.2 ml. (0.03 mole) of chloroacetyl chloride. Thereaction solution was stirred at room temperature for 15 minutes and wasthen refluxed for one and one-half hours. Water and ether were added tothe cooled reaction solution and the aqueous phase drawn off anddiscarded. The ether layer was washed with water and aque ous sodiumcarbonate and finally water, after which the ether solution was dried(MgSO The solvent was removed to give N-phenyl-2-chloroacetyl-l,2,3,4-tetrahydro-6,7-dimethoxyl isoquinolinecarboxamide, which uponrecrystallization from boiling ethyl acetate was obtained as a whitesolid, m.p. 182.0-l 83.0 C. (dec.) (corr.).

16. Following the procedure described in A-lS hereinabove, butsubstituting N-(4-bromophenyl)methyll,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinecarboxamide for N-phenyll ,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinecarboxamide and substituting 2-bromo-2-methylpropionylbromide for chloroacetyl chloride there is obtained N-(4-bromophenyl)methyl-2-(2-bromo-2-methylpropionyl)- l,2,3,4-tetrahydro-6,7-dimethoxyl -isoquinolinecarboxamide.

alkanoyl); Xll, R

17. When the above described procedure of A-15 is followed, substitutingN-( 4-methoxyphenyl)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide for N-phenyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxamide andsubstituting 2-chloro-3-methylbutyryl chloride for chloroacetylchloride, there is obtained N-(4-methoxyphenyl)-2-(2-chloro-3-methylbutyryl)- l ,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide.

18. The application of procedure A-15 above to the reaction ofN-(4-butoxyphenethyl)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide with 2-bromo-2- methylpropionylbromide, furnishes N-(4butoxyphenethyl)-2-(2-bromo-2-methylpropionyl)-1,2,3,4-tetrahydro-k6,7-dimethoxy-1-isoquinolinecarboxamide. B. l-[N-(R')-N-(phenyl(CH),,,)]aminomethyl-2-(R )-l,2,3,4 -tetrahydro-6,7-dimethoxyisoquinolines[V,R and R H; 1X, R H, R lower-alkyl; X, R and R (a-halo lower- (a-halolower-alkanoyl), R phenyllower-alkyl].

1. A suspension of 3.8 g. (0.1 mole) of lithium aluminum hydride under250 ml. of tetrahydrofuran was stirred while 16.0 g. (0.052 mole) ofN-phenyl-l,2,3,4-tetrahydr-6,7- dimethoxy-l-isoquinolinecarboxamide wasadded in portions during 3 minutes. The mixture was stirred and refluxedfor 6 hours after which the excess lithium aluminum hydride wascarefully destroyed by the addition of ml. of water in 25 ml. oftetrahydrofuran. To the mixture was added 150 ml. of methylenedichloride and stirring was effected for 10 minutes. The solids werefiltered off with the aid of diatomaceous earth and the methylenedichloride solution dried (MgSO The solvent was removed and the residuecrystallized from absolute diethyl ether to give1-(N-phenyl)aminomethyl-l,2,3,4- tetrahydro-6,7-dimethoxyisoquinoline,m.p. 9l97 C. The monohydrochloride salt, prepared by treatment of thefree base with an ethyl alcohol solution of anhydrous hydrochloric acid,was obtained as a colorless white solid, mp. 206.0-2 08.0 C. (dec.)(corr.).

2. When 14.6 g. (0.042 mole) of N-(4-chloropheny1)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxamide is reducedwith 3.0 g. (0.08 mole) of lithium aluminum hydride under 200 ml. oftetrahydrofuran, following the procedure of B-l above, there is obtainedl-[N-(4- chlorophenyl )]aminomethyll ,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline as a solid, mp 79.582.5 C. Treating the base withan alcoholic solution of anhydrous hydrochloric acid gives themonohydrochloride salt, a colorless solid, mp. 186.0-192.4 C.(dec.)(corr.).

Proceeding in the manner described in Bl, using the appropriateN-[phenyl(CH ),,,]-2-(R)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide, the following l-[N- (pheny1-(CH),,,)]aminoethyl-2-(R )-1,2,3,4-tetrahydro-6,7- dimethoxyisoquinolinesare obtained:

3. l-[N-(4-dimethylaminophenyl)]aminomethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

4. 1-[N-(4-methylthiophenyl)]aminomethyl-l,2,3,4-tetrahydro-6,7-dimeth0xyisoquinoline.

5. 1-[N-(4-methylphenylmethyl)]aminomethy1-1,2,11,4-tetrahydro-6,7-dimethoxyisoquinolihe.

6. l-(N-phenethyl)aminomethyl-2-phenylmethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

7. 1-[N-(4-bromophenylmethyl)lmethylamino-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

8. l-[N-(4-butoxyphenethyl)]aminomethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

9. 1-[N-(3methoxyphenethy1)]aminomethyl- 1 ,2,3,4-

tetrahydro-6,7-dimethoxyisoquinoline.

10. A mixture of6.8 g. (0.023 mole) of 1-(N-pheny1)- aminomethyl- 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, 4.84 g. (0.026 mole) ofmethyl p-toluenesulphonate, and 3.2 g. (0.03 mole) of sodium carbonatein 75 ml. of acetonitrile was stirred and heated at reflux for 4 hours.To the cooled reaction mixture was added water and ether and the organiclayer drawn off. The aqueous layer was extracted with chloroform and thecombined organic extracts dried. The solvent was removed and the residuewas taken up in excess ethyl alcohol solution of anhydrous hydrochloricacid. Upon standing, there separated 1-(N-phenyl)aminomethyl-Z-methyl-1,2,3,4-tetrahydro-6,7-dimethyoxyisoquinoline in the form of thedihydrochloric acid-addition salt, a colorless solid, mp. 202.0-203.0 C.(dec.)(corr.), after recrystallization from methanol.

1 1. When N-phenyl-Z-methyl- 1 ,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide is reduced with lithium aluminumhydride, according to B-] hereinabove, and the base is treated withexcess ethyl alcohol solution of anhydrous hydrochloric acid, there isobtained l-(N-phenyl )aminomethyl-2-methyll,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline in the form of thedihydrochloric acid-addition salt having the same melting point as thatobtained in 13-10 above.

12. Following the procedure of 13-10 above, 13.3 g. (0.04 mole) of1-[N-(4-ch1orphenyl)]aminomethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, 8.2 g. (0.044 mole) of methylp-toluenesulphonate and 5.3 g. (0.05 mole) of sodium carbonate in 125ml. of acetonitrile was reacted to give l-[N-(4-chlorophenyl)]aminomethyl-2-methyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, a colorless solid, mp. 78.0-79.0 C., afterrecrystallization from ether-hexane.

13. To a solution of 23.84 g. (0.08 mole) of l-(N-phenyl)aminomethyll,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline in 250 ml. of acetonitrileand containing 10.6 g. (0.1 mole) of sodium carbonate, there was addedduring minutes in a dropwise manner 10.54 g. (0.083 mole) of benzylchloride in 10 ml. of acetonitrile. The reaction mixture was stirred andrefluxed for four hours after which it was cooled, followed by theaddition of water. The acetonitrile layer was separated and the aqueousphase was extracted with chloroform. The combined organic solutions weredried and upon removal of the solvent the residue was taken up inabsolute ethyl alcohol and the solution diluted with anhydrous ether. Asolid separated and was collected and dried to give 1-(N-phenyl)aminomethyl-2-pheny1methy1-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, m.p. 102-106 C. An acetone solution of thebase was treated with an excess of an ethyl a1- cohol solution ofanhydrous hydrochloric acid to give the dihydrochloride salt, acolorless solid, mp. 212.2214.0 C. (dec.)(corr.).

14. Using the procedure described in B-13 hereinabove, 41.5 g. (0.125mole) of 1-[N-(4-chlorophenyl)aminomethyl]l,2,3,4-tetrahydro-6,7-dimeth0xyisoquino1ine were treated with 16.5 g.(0.130 mole) of benzyl chloride in 20 ml. of acetonitrile in thepresence of 15.9 g. (0.15 mole) of sodium carbonate. The base wastreated with an ethyl alcohol solution of anhydrous hydrochloric acid togive1-[N-(4-chlorophenyl)]aminomethyl-2-phenylmethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline dihydrochloride, m.p. l93.0194.6 C. (dec.)(corr.).

Following the procedure of B-13 above and employing the appropriate "l'(p y x-(Pnenuucm)ml y 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline, thefollowing 1-[N-(phenyl(CH ,)]-aminomethyl-Z-phenylmethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolines are obtained.

15. 1-[N-(4-butoxyphenethyl)]aminomethyl-2-pheny1-methyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

16.1[N-(4-bromophenylmethyl)laminomethyl-Z-phenylmethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

l7.l-[N-(4-dimethylaminophenyl)]aminomethyl-2-phenylmethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

18. 1-[N-( 3-methoxyphenethyl)]aminomethyl-2-phenylmethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

19. An ice bath cooled solution of 15.52 g. (0.04 mole) of 1- N-phenyl)aminomethyl-Z-phenylmethyhl ,2,3,4-tetrahydro-6,7-dimethoxyisoquino1ine in 75 ml. of methylene dichloride was treatedwith 4.0 ml (0.053 mole) of chloroacetyl chloride over a period of 20minutes. The cooling bath was removed and after 30 minutes the reactionmixture was refluxed for 2 hours. The reaction mixture was diluted withan equal volume of absolute ether causing l[N-(ch1oroacety1)-N-(phenyl)]aminomethyl-Z-phenylmethyl-1 ,2,3 ,4-tetrahydro-6,7-dimethoxyisoquinoline to separate as the monohydrochloride salt, acolorless solid, mp. 15l.0-l54.0 C. (corn), after recrystallization fromethyl alcohol-ether.

When the procedure of B-l9 above is followed in reacting the appropriatel-[ N-( phenyl( CH]aminomethyl-2-phenylmethyl-l,2,3,4-tetrahydro-6,7-dimethoxyisoquinolinewith the appropriate a-halo lower-alkanoyl halide the followingcompounds named as the free base form, are obtained:

20. 1-[N-( 2-bromo- 2-methylpropionyl )-N-(4-bromophenylmethyl)]aminomethyl-Z-phenylmethyl-1,2,3 ,4-tetrahydro-6,7-dimethoxyisoquinoline.

21. 1-[N-(2-chloro-3-methylbutyryl)-N-(4-butoxyphenethyl)]aminomethyl-Z-phenylmethyl-1,2,3,4- tetrahydro-6,7-dimethoxyisoquinoline.

22. l[N-(chloroacetyl-N-(4-chlorophenyl)]amino methyl- Z-phenylmethyll,2,3 ,4-tetrahydro-6,7-dimethoxyisoq uinoline.

23. 1 -[N-( 2-chloro3-methylvalery1)-N-( 3-methoxyphenethyl]aminomethyl-2-phenylmethyll ,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

24. l-[N-(2-bromo-2-methylpropionyl)-N-(4-dimethylaminophenyl)]aminomethyI-Z-phenylmethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

25. To a chilled, stirred solution of 2.98 g. (0.01 mole) of 1-(N-phenyl)aminomethyl-1,2,3 ,4-tetrahydro-6,7-dimethoxyisoquinoline in50 m1. of methylene dichloride containing 2.3 g. (0.022 mole) of sodiumcarbonate, there was added over 7 minutes 1.13 g. (0.01 mole) ofchloroacetyl chloride. The cooling bath was removed and the reactionmixture stirred for 30 minutes, followed by reflux for hours. Thereaction was diluted with water and then extracted with an excess ofaqueous hydrochloric acid. The organic layer was separated and dried.The solvent was removed and the residue was taken up in hot absoluteethyl alcohol. On standing l-[N-(chloroacetyl)-N-(phenyl)]aminomethyl-2-chloroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline separated, which aftercollection and recrystallization from boiling ab.- solute ethyl alcoholgave a colorless solid, mp. 179.0l 80.2 C. (dec.)(corr.).

C. Ethyl 2-(a-halo 1ower-alkanoy1)-l ,2,3,4-tetrahydro-6,7- dimethoxy- 1-isoq uinolinecarboxylates (XVI).

1. To a stirred solution of 63.0 g. (0.24 mole) of ethyl 1 ,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxylate in 360 ml. ofchloroform there was added during 45 minutes, 30 ml. (0.40 mole) ofchloroacetyl chloride. The cooling bath was removed and stirringcontinued for one and one-quarter hours after which the reaction washeated at reflux for 3 hours. The solvent was removed and the residuewas taken up in benzene and washed successively with water, aqueoussolution of sodium bicarbonate, and finally water. The organic layer wasdried and the solvent removed. The residue was taken up in anhydrousether from which solution ethyl 2- chloroacetyll,2,3,4-tetrahydro-6,7-dimethoxy- 1 -isoquinolinecarboxylate separatedand after collection and recrystallization from boiling absolute ethylalcohol with the aid of decolorizing charcoal, was obtained as acolorless solid, mp. 80.684.2 C. (corr.).

2. Following the procedure described in C-l above, but substituting2-bromo-2-methylpropionyl bromide for the chloroacetyl chloride used inthat example, there is obtained ethyl 2-(2-bromo-2-methylpropionyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate.

3. When 2-ch1oro-3-methylbutyryl chloride is substituted forchloroacetyl chloride as used in C-l hereinabove, there is obtainedethyl 2-( Z-chloro-3-methylbutyryl)-l ,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate.

4. Using the procedure of C-1 hereinabove, but substituting2-bromo-2-methylbutyryl bromide for chloroacetyl chloride in reactionwith ethyl l,2,3,4-tetrahydro-6,7-dimethoxy-lisoquinolinecarboxylate,the product obtained is ethyl 2-(2- bromo-2-methylbutyryl)-1,2,3,4-tetrahydro-6,7-dimethoxyl isoquinolinecarboxylate.

5. Following the procedure of C-1 hereinabove, but substituting2-chloro-3-methylvalery1 chloride for chloroacetyl chloride used in thatexample, there is obtained ethyl 2- chloro-3-methylvaleryl)- l ,2,3,4-tetrahydro-6,7-dimethoxyl-isoquinolinecarboxylate.

D. 3-Oxo-2-[pheny1(Cl-l ),,,]-4-(R,R )-1,3,4,6,7,1lb-hexahydro-9,10-dimethoxy-2l-l-pyrazino[2,1-a]isoquinolines. (X- IV).

1. A solution of 32 g. of 1-[N-(Chloroacetyl)N-(phenyl)]aminomethyl-2-phenylmethyl-1,2,3 ,4-tetrahydro-6,7-dimethoxyisoquinoline in ml. of absolute ethyl alcohol was refluxed for1616 The reaction mixture was then subjected to catalytic hydrogenationusing 10 percent palladium on charcoal as the catalyst. The catalyst wasremoved by filtration and the alcohol solution concentrated in vacuo.The residue was dissolved in water and treated with a slight excess ofan aqueous solution of sodium hydroxide. The oil that separated wasextracted with chloroform, and the chloroform extract dried. The solventwas removed and the residue recrystallized from boiling absolute ethylalcohol to give 3- oxo-2-phenyl-l ,3,4,6,7,1 lb-hexahydro-9, lO-dimethoxy-ZH- pyrazino[2,1-a]isoquinoline, a colorless solid, m.p.l71.8-l 73.4 C. (corr.).

2. Following the procedure described in E1 above, l-[N-(chloroacetyl)-N-(4-ch1orophenyl)]aminomethyl-2-pheny1-methyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline was heated for 16hours in absolute ethyl alcohol solution and without isolation, thecyclized product was catalytically reduced to give3-oxo-2-(4-chlorophenyl)-1,3,4,6,7,1lb-hexahydro9,10-dimethoxy-2-H-pyrazino[2,1-a]isoquinoline,m.p. l75.6l79.6 C. (corr.).

3. Substituting 1-[N-(2-bromo-2-methy1propionyl)-N-(4-bromophenylmethyl)]aminomethyl-Z-phenylmethyl-1,2,3,4-tetrahydro-6,7-dimethoxyiosquinoline for l-[N- (chloroacetyl)-N-(phenyl)]aminomethyl-2-phenylmethyl-1,2,3,4-tetrahydro-6,Idimethoxyisoquinoline, there is obtained byfollowing the procedure of E-l above, 3-oxo-2-(4-bromophenylmethyl)-4-dimethyl-l ,3,4,6,7,l lb-hexahydro- 9, l0-dimethoxy-2H-pyrazino[2,1-a]isoquinoline.

4. Applying the procedure of E-l hereinabove, to l-[N-(2-chloro-3-methy1butyryl)-N-(4-butoxyphenethyl)] aminomethyl2-phenylmethyll ,2,3,4-tetrahydro-6,7- dimethoxyisoquinoline, gives3-oxo-2-(4-butoxyphenethyl)-4- isopropyll ,3,4,6,7,1 lb-hexahydro-9, lO-dimethoxy-ZH- pyrazino[2,1-a]isoquinoline.

5. Using the procedure of E-l hereinabove, but substituting 1-[N-(2-chloro-2-methylbutyryl)-N-( 3-methoxyphenethyl)]aminomethyl-2-phenylmethyl-1,2,3,4-tetrahydro-6,7- dimethoxyisoquinolinefor l-[N-(chloroacetyl)-N-(phenyl)] aminomethyl-2-phenylmethyll ,2,3,4-tetrahydro-6',7- dimethoxyisoquinoline used in that procedure, thereis obtained .3-oxo-2-( 3-methoxyphenethyl)-4-methyl-4-ethyl- 1,3,4,6,7,llb-hexahydro-9,l0-dimethoxy-2l-l-pyrazino[2,l a]isoquinoline.

6. When l-[N-( 2-bromo-2-methylpropionyl)-N-(4-dimethylaminophenyl)]aminomethyI-Z-phenylmethyl-1,2, 3 ,4-tetrahydro-6,7-dimethoxyisoquinoline is substituted for l-[N-(chloroacetyl)-N-(phenyl)]aminomethyl-2-phenylmethyl- 1,2,3,4-tetrahydro6,7-dimethoxyisoquinoline in the procedure of E-l described hereinabove,the product obtained is 3-oxo-2-(4-dimethy1aminophenyl)-4dimethyll,3,4,6,7,1 lb-hexahydro-9,l0-dimethoxy-2H-pyrazino[2,1-a]isoquinoline.

E. 1,4-Dioxo-2[pheny1(CH ),,,]-3-(R,R)-l,3,4,6,7,1lb-hexahydro-9,10-dimethoxy-2l-l-pyrazino[2,l-a]isoquinolines(XV).

1. A mixture of 20.5 g. (0.06 mole) of ethyl 2-chloroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxyl -isoquinoline carboxylate, 14.0 g.(0.15 mole) of aniline and 10 ml. of diethylene glycol monoethyl etherwas refluxed for 30 hours. To the cooled reaction mixture was addedchloroform, water, and an aqueous solution of hydrochloric acid. Thechloroform layer was separated and the aqueous layer extracted withadditional fresh chloroform. The combined organic extracts were driedand the solvent removed. The residue was recrystallized successivelyfrom absolute ethyl alcohol, ethyl acetate, and absolute ethyl alcoholto give 1,4-dioxo-2-phenyl-1,3,4,6,7,11bhexahydro-9,10-dimethoxy-2H-pyrazino-[2,1-a]isoquinoline, a paleyellow solid, mp. l77.2-181.0 C. (corr.).

2. A mixture of 1.68 g. (0.0043 mole) of N-phenyl-Z-chloroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinoline-carboxamideand 1.0 g. (0.002 mole) ofsodium hydride, suspended in 40 ml. of toluenewas refluxed for four and onehalf hours. To the cooled mixture wascarefully added 25 ml. of water and stirring was effected for fifteenminutes. The benzene layer was separated and the aqueous layer extractedwith chloroform. The dried organic layer was then concentrated in vacuoand the residue taken up in boiling absolute ethyl alcohol. On coolingl,4-dioxo-2-phenyl-1,3,4,6,7,11bhexahydro-9,10-dimethoxy-2H-pyrazino[2,1-]isoquinolinecrystallized and after collection and recrystallization from absoluteethyl alcohol was obtained as a pale yellow solid having the samemelting point as the material obtained in F-1 above.

3. Following the procedure of F-2, but substituting N-(4-bromophenyl)methyl-2-(2-bromo-2-methylpropionyl)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide forN-phenyl-Z-chloroacetyll ,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxamide used in that procedure, there isobtained 1,4-dioxo-2-(4-bromophenylmethyl)-3-dimethyl-l ,3,4,6,7,l1b-hexahydro-9,lO-dimethoxy-2H-pyrazino-[2,l-a]isoquinoline.

4. Applying the procedure of F-2 hereinabove to N-(4-methoxyphenyl)-2-(2-chloro-3-methylbutyryl)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxamide, there is obtainedl,4-dioxo-2-(4-methoxyphenyl)-3-isopropyl-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2l-l-pyrazino[2,1-a]isoquinoline.

5. A mixture of 54.7 g. (0.16 mole) of ethyl2-chloroacetyll,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinoline-carboxylateand 49.2 g. (0.40 mole) of 2-methoxyaniline in 320 ml. of diethyleneglycol monoethyl ether was reacted according to the procedure of F-lhereinabove to obtain 1,4-dioxo-2-(2- methoxyphenyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2 H-pyrazino[2,1-a]isoquinoline, a colorlesssolid, mp. 171.01 74.0 C. (corr.).

6. Using the procedure of F-l hereinabove, but substituting3-methoxyaniline for the aniline used in that procedure there wasobtained1,4-dioxo-2-(3-methoxyphenyl)-1,3,4,6,7,llbhexahydro-9,10-dimethoxy-2H-pyrazino[2,1-a]isoquinoline,a pale yellow solid, m.pv l36-142 C.

7. Substituting 4-methoxyaniline for aniline and using the procedure ofFl described above, 1,4-dioxo-2-(4-methoxyphenyl)-1,3,4,6,7,llb-hexahydro-9,IO-dimethoxy-ZH- pyrazino[2, l -a]isoquinoline, m.p.l64-l 69 C. is obtained.

8. Applying the procedure of F-l hereinabove, to the reaction of ethyl2-( 2-bromo-2-methylbutyryl)-l,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxylate with 4-dimethylaminophenethylamine, there is obtained 1,4-dioxo-2-(4-dimethylaminophenethyl)-3-methyl-3-ethyl-1,3,4,6,7,l1bhexahydro-9, l0-dimethoxy-2H-pyrazino[2, l -a]isoquinoline.

9. Reaction of ethyl 2-(2-chloro-3-methylvaleryl)-l,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate with 4-methylthiophenylmethylamine, according to the procedure F-l hereinabove,gives l,4-dioxo-2-(4-methylthiophenylmethyl)-3-( 2-butyl)-1,3,4,6,7,l1b-hexahydro-9,10-dimethoxy-2H-pyrazino-[2,1-a]isoquinoline.

10. When 34.2 g. (0.1 mole) of ethyl 2-chloro acetyl-1,2,3,4-tetrahydro-6,7-dimethoxyl -isoquinolinecarboxylate and 26.8 g.(0.25 mole) of benzylamine in 200 ml. of diethylene glycol monoethylether are reacted according to the procedure of F-l describedhereinabove, there is obtained1,4-dioxo-2-phenylmethyl-l,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-pyrazino[2,l-ajisoquinoline as a colorless solid, mp131.0132.0 C. (corr.).

11. Following the procedure of F-l, described above, but substitutingphenethylamine for aniline used in that procedure, there is obtained1,4-dioxo-2-phenethyl- 16 l,3,4,6,7,1lb-hexahydro9,l0-dimethoxy-2H-pyrazino[2,la]isoquinoline as a colorlesssolid, mp. 200.5205.5 C.

12. Using the procedure of F-l hereinabove, but substituting ethyl2-(2-bromo-2-methylbutyryl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquino1inecarboxylate for ethyl 2- chloroacetyl- 1,2,3,4-tetrahydro-6,7-dimethoxyl -isoquinoline-carboxylate andsubstituting 4-chlorophenethylamine for aniline used in that procedure,the product obtained is 1,4-dioxo-2-(4-chlorophenethyl)-4-methyl-3-ethyll ,3,4,6,7,1 1bhexahydro-9,lO-dimethoxy-ZH-pyrazinol2, 1 -a]isoquinoline.

13. WhenN-(4-butoxyphenethyl)-2-bromo-2-methylpropionyl)-1,2,,3,4-tetrahydro-6,7-dimethoxy-lisoquinolinecarboxamideis reacted with sodium hydride, according to the procedure described inF-2 hereinabove, there is obtained,1,4-dioxo-2-(4-butoxyphenethyl)-3-dimethyl-1,3,4,6,7,11bhexahydro-9,10-dimethoxy-2H-pyrazino[2,l-a]isoquinoline.

EXAMPLE 1 A suspension of 4.6 g. (0.12 mole) of lithium aluminum hydridein 200 ml. of tetrahydrofuran was stirred during the addition of 10.3 g.(0.03 mole) of 3-oxo-2-phenyl-l ,3,4,6,7,1 1b-hexahydro-9,10-dimethoxy-2H-pyrazino-[2,l-alisoquinoline. The reactionmixture was then heated at reflux for 5 hours after which 10 ml. ofwater in 25 ml. of tetrahydrofuran was added. After hydrolysis, themixture was stirred with ml. of chloroform and then filtered with theaid of diatomaceous earth. The organic layer was dried (MgSO,,) and thesolvent removed. The residue was taken into acetone and the solutiontreated with an ethyl alcohol solution of anhydrous hydrochloric acid togive 2-phenyl-l,3,4,6,7,1 lb-hexahydro-9,10-dimethoxy-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, a light tansolid, mp. 219.5221.0 C. (dec. )(corr.), after recrystallization fromethyl alcohol-ether.

EXAMPLE 2 Employing a procedure similar to that described in Example 1and using the appropriate 3-oxo-2-[phenyl (CH ),,,]-4- (R R)-l,3,4,6,7,l 1b-hexahydro-9,10-dimethoxy-2H- pyrazino[2, l-a]isoquinoline, there are obtained:

a. 2-(4Chlorophenyl)-1,3,4,6,7,l lb-hexahydro-9, l 0-dimethoxy-2H-pyrazino[2,l-a]isoquinoline, m.p. l58.4-l 60.0 C. (corr.).

b. 2-(4-Bromophenylmethyl)-4-dimethyl-1,3,4,6,7,1 lbhexahydro-9, 10-diemthoxy-2H-pyrazino[ 2, 1 -a]isoquinoline.

c. 2-( 4-Butoxyphenethyl)-4-isopr0pyl-l ,3,4,6,7,1lb-hexahydro-9,10-dimethoxy-2Hpyrazino[2,1-a]isoquinoline.

d. 2-( 3-Methoxyphenethyl)-4-methyl-4-ethyl- 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-pyrazino[2,1- a]isoquinoline.

e. 2-( 4-Dimethylaminophenyl)-4-dimethyl-l ,3,4,6,7,11bhexahydro-9,l0-dimethoxy-2H-pyrazino[2,1-a]isoquinoline.

EXAMPLE 3 To a stirred suspension of 3.8 g. (0.1 mole) of lithiumaluminum hydride in 150 ml. of tetrahydrofuran was added 7.25 g. (0.019mole) of1,4-dioxo-2-phenethyl-l,3,4,6,7,1lb-hexahydro-9,10-dimethoxy-2H-pyrazino[2,l-a]isoquinoline.The reaction mixture was refluxed for five hours after which the excesslithium aluminum hydride was decomposed by the addition of 10 ml. ofwater in 25 ml. of tetrahydrofuran and finally 5 ml. of water. To themixture, there was then added 200 ml. of chloroform and stirringcontinued for 15 minutes. Filtration was carried out with the aid ofdiatomaceous earth and the organic filtrate dried. The solvent wasremoved and the residue taken into 25 ml. of absolute ethyl alcohol. Thealcohol solution was treated with an ethyl alcohol solution of anhydroushydrochloric acid to give 2- phenethyl-1,3,4,6,7,1 lbhexahydro-9, l0-dimethoxy-2H-pyrazino-[ 2, 1 -a]isoquinoline dihydrochloride, anoff-white solid, mp. 276.0-278.0 C. (dec.) (corn), afterrecrystallization from ethyl alcohol.

Following a procedure similar to that described in Example 3, and usingthe appropriate l,4-dioxo-2[phenyl(CH ),,,]-3- R,R )-l,3,4,6,7,l lbhexahydro-9,lO-dimethoxy-ZH- pyrazino-[2, 1-a]isoquinoline, there areobtained:

a. 2-phenylmethyl-l ,3,4,6,7,1 lb-heXahydro-9, lO-dimethoxy-2-H-pyrazino[2,l-a]isoquinoline dihydrochloride, m.p.262.8264.0C. (dec.) (corn).

b. 2-Phenyll ,3,4,6,7,l 1b-hexahydro-9, l O-dimethoxy-ZH-pyrazino[2,l-a]isoquinoline dihydrochloride, m.p. 207-2l8 C. (dec.)(corn). A mixed melting point determination of this compound with thatobtained by the procedure of Example 9, shows no melting pointdepression.

(2. 2-( 2-Methoxyphenyl)- l ,3,4,6,7,l lb-hexahydr-9,10-dimethoxy-2H-pyrazino[ 2, l -a]isoquinoline dihydrochloride, m.p.225.0228.0 C. (dec.)(corr.).

d. 2-(2-Methoxyphenyl)-l,3,4,6,7,l lb-hexahydro-9,l0-diemthoxy-2H-pyrazino[ 2, l -a]isoquinoline dihydrochloride, m.p.198.0-l998 C. (dec.)(corr.).

e. 2-(4-Methoxyphenyl)- l ,3,4,6,7,l lb-hexahydro-9, 1 0-dimethoxy-2Hpyrazino[2,l-a]isoquinoline dihydrochloride, m.p.233.0-234.5" C. (dec.)(corr.).

f. 2-(4-Bromophenylmethyl)-3-dimethyll ,3,4,6,7,l lb-hexahydro-9, l0-dimethoxy-2H-pyrazino[ 2, l -a]isoquinoline.

g. 2-(4-Methoxyphenyl)-3-isopropyll ,3,4,6,7,llbhexahydro-9,10-dimeth0xy-2H-pyrazino[2,1-a]isoquinoline.

h. 2-(4-Dimethylaminophenethyl)-3-methyl-3-ethyll,3,4,6,7,llb-hexahydro-9, l 0-dimethoxy-2H-pyrazin0[ 2, l alisoquinoline.

i. 2-(4-Methylthiophenylmethyl)-3-( 2-butyl)-l ,3,4,6,7,l lbhexahydro-9,l 0 dimethoxy-2H-pyrazino[ 2, l -a]isoquinoline.

j. 2-(4-Butoxyphenethyl)-3-dimethyll ,3,4,6,7,l lb-hexahydro-9, lO-dimethoxy-2H-pyrazino[ 2, l -a]isoquinoline.

k. 2-(4-Chlorophenethyl)-3-methyl-3-ethyll ,3,4,6,7,llbhexahydro-9,10-dimethoxy-2H-pyrazino[2, l-a]isoquinoline.

Our new compounds can exist in stereochemically isomeric forms, that is,optical isomers and geometric isomers. If desired, the isolation or theproduction of a particular sterochemical form can be accomplished byapplication of the general principles known in the prior art.

We claim:

1. Ethyl 2-(amonohalo lower-alkanoyl)-l ,2,3,4 tetrahydro-6,7-dimethoxy-l-isoquinolinecarboxylate of the formula H3C0 l b-(whalelower-alkanoyl) C H 300 C H 2. Ethyl 2chloroacetyl-l,2,3,4-tetrahydro-6,7-dimethoxy- 1-isoquinolinecarboxylate accordingto claim l.

*l l k

2. Ethyl 2-chloroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinecarboxylate according toclaim 1.